Method of treatment with tradipitant

ABSTRACT

This application relates to a method of treatment with the NK-1 antagonist, tradipitant.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of co-pending U.S. patent applicationSer. No. 16/944,596, filed 31 Jul. 2020, which is a continuation of U.S.patent application Ser. No. 16/430,514, filed 4 Jun. 2019 and issued asU.S. Pat. No. 10,772,880, which is a continuation of U.S. patentapplication Ser. No. 15/553,394, filed 24 Aug. 2017 and issued as U.S.Pat. No. 10,463,655 on 5 Nov. 2019, which is a US national stage under35 USC § 371 of International Patent Application No. PCT/US2016/021015,filed 4 Mar. 2016, which in turn claims the benefit of U.S. ProvisionalApplications No. 62/128,472, filed 4 Mar. 2015, and No. 62/232,644,filed 25 Sep. 2015, each of which is incorporated herein as though fullyset forth.

BACKGROUND

Chronic pruritus affects millions of people worldwide and represents aserious and unmet medical need. The itch sensation is believed to beinduced at least in part through the action of the endogenousneuropeptide substance P (SP), through the binding at NK-1Rs expressedon multiple skin cells.

The NK-1R is expressed throughout different tissues of the body, withmajor activity found in neuronal tissue. SP and NK-1R interactions inneuronal tissue regulate neurogenic inflammation locally and the painperception pathway through the central nervous system. Other tissues,including endothelial cells and immune cells, have also exhibited SP andNK-1R activity. The activation of NK-1R by the natural ligand SP isinvolved in numerous physiological processes, including the perceptionof pain, behavioral stressors, cravings, and the processes of nausea andvomiting. An inappropriate over-expression of SP either in nervoustissue or peripherally could result in pathological conditions such assubstance dependence, anxiety, nausea/vomiting, and pruritus. An NK-1Rantagonist may possess the ability to reduce this over-stimulation ofthe NK-1R, and as a result address the underlying pathophysiology of thesymptoms in these conditions.

Tradipitant is a neurokinin-1 receptor antagonist formerly known asVLY-686, having the chemical names2-[1-[[3,5-bis(trifluoromethyl)phenyl]methyl]-5-(4-pyridinyl)-1H-1,2,3-triazol-4-yl]-3-pyridinyl](2-chlorophenyl)-methanoneand{2-[1-(3,5-Bistrifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone,and the following chemical structure:

Tradipitant is disclosed in U.S. Pat. No. 7,320,994, and contains sixmain structural components: the 3,5-bis-trifluoromethylphenyl moiety,two pyridine rings, the triazol ring, the chlorophenyl ring and themethanone. Crystalline Forms IV and V of tradipitant are disclosed inU.S. Pat. No. 7,381,826. A process for synthesizing tradipitant isdisclosed in U.S. Pat. No. 8,772,496.

BRIEF DESCRIPTION OF THE INVENTION

A first aspect of the disclosure provides a method of administeringtradipitant to a patient in need thereof which comprises internallyadministering to the patient tradipitant in an amount and at a frequencyof administration sufficient to achieve and to maintain a plasmaconcentration of >100 ng/mL.

A second aspect of the disclosure provides a method of administeringtradipitant to a patient in need thereof which comprises internallyadministering an effective amount of tradipitant to the patient. Theeffective amount may be, e.g., 100 to 400 mg/day, 100 to 300 mg/day, or100 to 200 mg/day. The effective amount may be administered twice daily,i.e., 50 to 200 mg bid, 50 to 150 mg bid, 50 to 100 mg bid, or about 85mg bid.

A third aspect of the disclosure provides a use of tradipitant for thetreatment of pruritus by internally administering to a patient sufferingfrom pruritus by internally administering to the patient tradipitant inan amount and at a frequency of administration sufficient to achieve andto maintain a plasma concentration of >100 ng/mL, i.e., an effectiveamount of tradipitant.

A fourth aspect of the disclosure provides a use of tradipitant for thepreparation of a medicament for the treatment of pruritus by internallyadministering to the patient tradipitant in an amount and at a frequencyof administration sufficient to achieve and to maintain a plasmaconcentration of >100 ng/mL, i.e., an effective amount, e.g., an amountof 85 mg bid, 85 mg qd, 100 mg qd, or other dosing regimen.

In further aspects of the invention, the dose can be 85 to 170 mg/day.This may be, e.g., 85 mg bid, 85 mg qd, 100 mg qd, or 100 mg bid.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a scatter plot of serum levels of tradipitant, showingconcentration weight vs. visit time.

FIG. 2 provides a scatter plot of VAS change vs. concentration-weight oftradipitant (Spearman correlation P-value=0.0204).

DETAILED DESCRIPTION OF THE DISCLOSURE

At least one embodiment of the present invention is described below inreference to its application in connection with the use of tradipitantfor the treatment of chronic pruritus. Although embodiments of theinvention are illustrated relative to specific dosing regimens, e.g.,100 mg qd, 85 mg bid, and 85 mg qd, it is understood that the teachingsare equally applicable to other dosing regimens, e.g., 100 to 400mg/day, 100 to 300 mg/day, 100 to 200 mg/day, or about 85-170 mg/day,which may be administered as, e.g., 50 to 200 mg bid, 50 to 150 mg bid,50 to 100 mg bid, or about 85 mg bid.

As used herein, the term “patient” refers to a mammal that is afflictedwith one or more disorders ameliorated by administration of tradipitant,e.g., pruritus. Guinea pigs, dogs, cats, rats, mice, horses, cattle,sheep, and humans are examples of mammals within the scope of themeaning of the term. It will be understood that the most preferredpatient is a human.

It is also recognized that one skilled in the art may affect thedisorders by treating a patient presently afflicted with the disordersor by prophylactically treating a patient afflicted with the disorderswith an effective amount of tradipitant. Thus, the terms “treatment” and“treating” are intended to refer to all processes wherein there may be aslowing, interrupting, arresting, controlling, or stopping of theprogression of the disorders described herein, and is intended toinclude prophylactic treatment of such disorders, but does notnecessarily indicate a total elimination of all disorder symptoms.

As used herein, the term “effective amount” of tradipitant refers to anamount that is effective in treating the disorders described herein.

With regard to dosing, “qd” refers to dosing once per day; bid dosingtypically means dosing once in the morning and once in the evening,generally no less than about 8 hours or more than about 16 hours apart,e.g., 10 to 14 hours or 12 hours (Q12H).

The skilled artisan will appreciate that additional preferredembodiments may be selected by combining the preferred embodimentsabove, or by reference to the examples given herein.

Example 1

A phase II proof of concept clinical study (Study ID VP-VLY-686-2101,“Proof of Concept of VLY-686 in Subjects With Treatment-ResistantPruritus Associated With Atopic Dermatitis”) was conducted,investigating the safety and efficacy of tradipitant as a monotherapy inthe treatment of chronic pruritus in patients with atopic dermatitis.

Despite a highly significant and clinically meaningful improvement frombaseline by tradipitant (40.5 mm improvement from baseline, p<0.0001) asmeasured on a 100 mm unit Visual Analog Scale (VAS) for itch, a veryhigh placebo effect (36.5 mm improvement from baseline, p<0.0001) on thechange from baseline led to no statistical difference from placebo.However, subsequent analysis of population PK samples across allpatients in the study revealed significant and clinically meaningfulresponses across multiple outcomes evaluated in individuals with higherlevels of tradipitant exposure at the time of their pruritusassessments.

The pre-specified primary endpoint of the Phase II proof of conceptclinical study was the change from baseline on the Visual Analog Scale(VAS) for itch. Due to high placebo effect, there was no significantdifference from placebo on this pre-specified endpoint. However, insubsequent analyses it has been discovered that there is an exposureresponse relationship. It has further been observed that there is asignificant and clinically meaningful response across several pruritusrelated outcomes evaluated in individuals with higher blood plasmalevels of tradipitant. Based on the data examined across the study,lower blood plasma levels of tradipitant may be below a threshold ofefficacy to ameliorate the itch sensation in patients.

Methods

In the study, patients with a Visual Analog Scale (VAS) score of greaterthan 70 mm during one of the two days preceding inclusion into the studywere randomized to receive orally either 100 mg of tradipitant (N=34) orplacebo (N=35) once a day in the evening. In the tradipitant arm of thestudy, tradipitant was orally administered to patients in capsules withstandard excipients in an amount of 100 mg in the evening. Clinicalassessments were made after 3 or 4 weeks of daily treatment, or at both3 weeks and 4 weeks, each assessment being done in the morning of theday after last treatment or in the afternoon of the day after lasttreatment. The tradipitant was administered in an immediate release formcomprising tradipitant and pharmaceutically acceptable excipients in acapsule. The tradipitant particle size was approximately: D₁₀: <5 um,D₅₀: <10 um, and D₉₀: <25 um, wherein D₁₀ means that 10% of theparticles are of the indicated mean particle size, D₅₀ means that 50% ofthe particles are of the indicated mean particle size, and D₉₀ meansthat 90% of the particles are of the indicated mean particle size.

Baseline VAS scores were 76.1 and 77.2 for the tradipitant and placeboarms respectively. Efficacy was evaluated through a number of clinicalresearch instruments. In addition, at the time of efficacy evaluationblood samples were collected for PK analysis in order to determine theplasma levels of tradipitant.

Results

A PK-PD (pharmacokinetic-pharmacodynamics) analysis in the tradipitanttreatment arm showed a significant correlation between blood levels oftradipitant and the VAS change from baseline (p<0.05). Individuals withhigher circulating levels of tradipitant at the time of the efficacyevaluation demonstrated higher magnitude of response. A separate PKanalysis of the time of pruritus assessment revealed that approximatelyhalf the patients in the study came in for morning (AM group, ˜12 hourspost-dose) visits for their pruritus assessments and that these patientsalso had higher blood levels of tradipitant than those who came in theafternoon (PM group, ˜18 hours post-dose).

The average plasma concentrations of tradipitant across AM andPM-evaluated patients were between about 125 ng/mL and about 225 ng/mL.Patients evaluated in the afternoons (PM) (mean=about 20 hours post lastadministration) tended to have lower plasma concentrations oftradipitant than patients evaluated in the mornings (AM) (mean=about 15hours post last administration). The average plasma concentration in thePM group was about 125 ng/mL, and the average plasma concentration inthe AM group was about 225 ng/mL, the difference being largelyattributable to the length of time post administration. Moresignificantly, the results show a correlation between plasmaconcentration and efficacy, whereby patients in whom the plasmaconcentrations were >100 ng/mL (e.g., about 125 ng/mL or greater, about150 ng/mL or greater, about 175 ng/mL or greater, about 200 ng/mL orgreater, or about 225 ng/mL or greater) tended to show greater efficacythan patients with lower plasma concentrations.

A further analysis of the AM group revealed significant and clinicallymeaningful effects of tradipitant as compared to placebo and is shown inTable 1. Higher concentrations of tradipitant were associated withhigher efficacy in treating chronic pruritus in the study. A similaranalysis in the PM group showed no significant differences betweentradipitant and placebo.

TABLE 1 Group efficacy analysis of pruritus measures AM PM TradipitantPlacebo P- Tradipitant Placebo P- N = 18 N = 17 Diff value N = 13 N = 11Diff value Primary VAS Average −54 −30.3 −23.7 0.007 −28.8 −34.6 5.820.6701 change Secondary VAS Worst −47.9 −26 −21.9 0.0302 −32.3 −41.38.99 0.5153 change VRS change −1.46 −0.67 −0.79 0.0496 −1.29 −1.16 −0.130.7881 DLQI change −2.52 −2.87 0.35 0.8458 −5.45 −3.56 −1.89 0.2423 PBI1.47 0.73 0.74 0.0393 1.01 1.4 −0.39 0.4696 CGIC 2.46 3.61 −1.15 0.04972.47 2.29 0.19 0.7452 SCORAD −9.58 −4.36 −5.23 0.0027 −6.29 −7.18 0.880.7061 change Table 1 abbreviations: Visual Analog Scale (VAS), VerbalRating Scale (VRS), Dermatology Life Quality Index (DLQI), ClinicalGlobal Impression of Change (CGI-C), Patient Benefit Index (PBI),SCORing Atopic Dermatitis Index (SCORAD).

This data is consistent with the hypothesis that tradipitant, an NIK-1Rantagonist, may offer symptomatic relief in patients with pruritus (VAS,VRS, SCORAD subjective). Endpoints were also collected in the study thatcorrespond to the underlying disease (SKINDEX, SCORAD objective, EASIand DLQI). These results did not show any significant difference fromplacebo which would be expected from a drug targeting the symptom ofitch in a short-term 4-week study. Importantly, as pruritus, theintractable itching associated with atopic dermatitis, is the majorcomplaint of patients, the effects that were also seen in the CGI-Cscale and the PBI scales suggest a recognizable overall clinicallymeaningful effect from both the clinician and the patient perspective.

Conclusions

These data support the premise that in patients suffering pruritus,e.g., pruritus associated with atopic dermatitis, patients can betreated by orally administering tradipitant, e.g., Form IV or Form V (ora pharmaceutically acceptable salt thereof) in amounts and at a dosingfrequency required to achieve plasma concentrations of at least about100 ng/mL, e.g., 125 ng/mL or greater, 150 ng/mL or greater, 175 ng/mLor greater, 200 ng/mL or greater, or 225 ng/mL or greater. Such plasmaconcentration levels can be achieved, e.g., by orally administering thetradipitant in immediate release solid dosage forms once per day at ahigher dose or in immediate release forms with improved bioavailabilityor in controlled release forms, or by orally administering thetradipitant multiple times per day, e.g., twice or more times per day,at a lower dose in immediate release or controlled release forms. Whilethe study data show that an effective plasma concentration can beachieved at about 12-18 hours, e.g., about 15 hours, post treatment with100 mg/day tradipitant in solid form in immediate release capsules, itwill be appreciated that it may be possible to achieve effective plasmaconcentrations using different doses and/or different formulations,including but not limited to controlled release formulations.

In conclusion, while the study failed to show an overall effect of thepredefined dose of tradipitant for this study, primarily due to thelarge placebo effect, the study demonstrated a PK-response relationshipas well as significant benefits in the group of patients that wereevaluated at the time of higher blood concentrations of tradipitant. Inthis study tradipitant 100 mg qd was well-tolerated and the adverseevent profile was mild and similar to placebo.

Treatment of a patient can be continued until the patient's symptoms ofpruritus are ameliorated or eliminated, e.g., ameliorated such that thepatient is able to function more or less normally during wake time hoursand sleep more or less normally during sleep time hours.

As discussed above, data indicate that in patients suffering pruritus,e.g., pruritus associated with atopic dermatitis, patients can betreated by orally administering tradipitant. Further studies havedemonstrated the safety and efficacy of various dosing regimens.

Example 2

In one study, healthy subject participants were orally administered 85mg tradipitant on study day 3, and then 85 mg tradipitant Q12H on studydays 4-16. Plasma concentration levels of tradipitant were measured oneach of day 3, day 7, and day 11.

This study illustrated that administration of 85 mg tradipitant qd (onday 3) produced an average plasma concentration over hours 0-12 that wasabout 50% of the plasma concentration observed in the PM group inExample 1. On days 7 and 11, the average plasma concentration over hours0-12 following administration of 85 mg bid (specifically, Q12H)tradipitant was about 150% of the plasma concentration observed in thePM group in Example 1. The average plasma concentration over hours 0-12at each point was determined by dividing the AUC for hours 0-12 (in(hr.)×(ng/mL)) by 12 hours.

These results indicate that in patients suffering pruritus, e.g.,pruritus associated with atopic dermatitis, patients can be treated byorally administering tradipitant, e.g., Form IV or Form V (or apharmaceutically acceptable salt thereof) in an amount of 85 mg bid,e.g., 85 mg Q12H, in order to achieve plasma concentrations that aregreater than the 125 ng/mL observed in the PM group in Example 1.

EMBODIMENTS

In addition to other illustrative embodiments, this invention can beseen to comprise one or more of the following illustrative embodiments:

1. A method of administering tradipitant to a patient in need thereofwhich comprises internally administering to the patient tradipitant inan amount and at a frequency of administration sufficient to achieve andto maintain a plasma concentration of at least about 100 ng/mL, e.g.,about 125 ng/mL or greater, about 150 ng/mL or greater, about 175 ng/mLor greater, about 200 ng/mL or greater, or about 225 ng/mL or greaterfor the duration of the treatment regimen.

2. A method of administering tradipitant to a patient in need thereofwhich comprises internally administering to the patient tradipitant inan amount and at a frequency of administration sufficient to achieve andto maintain a plasma concentration equal to or greater than the plasmaconcentration in a study population of patients 12 to 18 hours followingoral administration of 100 mg tradipitant in an immediate release formfor the duration of the treatment regimen.

3. The method of embodiment 1 or 2 wherein the tradipitant is orallyadministered in a solid immediate release form such as a capsule ortablet comprising tradipitant and one or more pharmaceuticallyacceptable excipients.

4. The method of embodiment 1 or 2 wherein the tradipitant is orallyadministered in a solid controlled release form such as a capsule ortablet comprising tradipitant and one or more pharmaceuticallyacceptable excipients.

5. A method of administering tradipitant({2-[1-(3,5-bis-trifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone)to a patient in need thereof which comprises orally administering to thepatient tradipitant in a solid immediate release form such as a capsuleor tablet comprising tradipitant and one or more pharmaceuticallyacceptable excipients twice daily in an amount of 100 to 400 mg/d, 100to 300 mg/d, or 100 to 200 mg/d of tradipitant.

6. A method of administering tradipitant({2-[1-(3,5-bis-trifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone)to a patient in need thereof which comprises orally administering to thepatient tradipitant once daily in a solid immediate release form such asa capsule or tablet comprising tradipitant and one or morepharmaceutically acceptable excipients in an amount of 150 to 400 mg/d,150 to 300 mg/d, or 150 to 200 mg/d of tradipitant.

7. The method of any of the preceding embodiments wherein the patient isbeing treated with tradipitant for pruritus.

8. The method of any of the preceding embodiments wherein the patient isbeing treated with tradipitant for atopic dermatitis and/or chronicpruritus.

9. The method of any of the preceding embodiments wherein thetradipitant is in crystalline Form IV or Form V.

10. Tradipitant for use in any of the preceding methods of treatment.

11. A pharmaceutical composition comprising tradipitant for use in anyof the preceding methods.

12. Tradipitant for use in the manufacture of a pharmaceuticalcomposition comprising tradipitant for use in any of the precedingmethods.

13. A method of administering tradipitant to a patient in need thereofwhich comprises internally administering to the patient tradipitant inan amount and at a frequency of administration sufficient to achieve andto maintain a plasma concentration of >100 ng/mL.

14. The method of embodiment 13, wherein the plasma concentrationof >100 ng/mL is selected from the group consisting of: 125 ng/mL orgreater, 150 ng/mL or greater, 175 ng/mL or greater, 200 ng/mL orgreater, and 225 ng/mL or greater for the duration of the treatmentregimen.

15. The method of embodiment 13, wherein the internally administeringstep is orally administering.

16. A method of administering tradipitant to a patient in need thereofwhich comprises internally administering to the patient tradipitant inan amount of 85-170 mg/day.

17. The method of embodiment 16, further comprising internallyadministering to the patient tradipitant in an amount of 85 mg qd.

18. The method of embodiment 16, further comprising internallyadministering to the patient tradipitant in an amount of 85 mg bid.

19. The method of embodiment 16, further comprising internallyadministering to the patient tradipitant in an amount of 100 mg qd.

20. A method of administering tradipitant to a patient in need thereofwhich comprises internally administering to the patient tradipitant inan amount of 50 to 200 mg bid.

21. A method of administering tradipitant to a patient in need thereofwhich comprises internally administering to the patient tradipitant inan amount of 50 to 150 mg bid.

22. A method of administering tradipitant to a patient in need thereofwhich comprises internally administering to the patient tradipitant inan amount of 50 to 100 mg bid.

23. The method of any of embodiments 13-22, wherein the tradipitant isbeing administered to treat pruritus.

24. Tradipitant for use in the treatment of pruritus by internallyadministering to a patient suffering from pruritus by internallyadministering to the patient tradipitant in accordance with the methodof any of embodiments 13-22.

25. Tradipitant for use in the preparation of a medicament for thetreatment of pruritus by internally administering to the patienttradipitant in accordance with the method of any of embodiments 13-19.

From the above, it is apparent that the dose can be one that results inplasma concentration at about 12 hours post-dose of about 100 ng/mL toabout 225 ng/mL, including e.g., about 125, about 150, about 175, orabout 200 ng/mL.

Tradipitant can be administered for the treatment of pruritis in animmediate release form at a dose of 50 to 100 mg qd, e.g., 85 mg qd or100 mg qd. Twice daily (bid) dosing of tradipitant in immediate releaseforms at 50 to 100 mg allows achievement and maintenance of the targetplasma concentrations throughout a 24 hour period. Accordingly,administration of, e.g., 85 mg (immediate release) bid provides greaterand/or more sustained relief from the symptoms of pruritis than qddosing (immediate release) at the same or a higher dose.

What is claimed is:
 1. A method of administering tradipitant to apatient in need thereof which comprises: internally administering to thepatient tradipitant in an amount and at a frequency of administrationsufficient to achieve and to maintain a plasma concentration of greaterthan 100 ng/mL.
 2. The method of claim 1, wherein the plasmaconcentration of greater than 100 ng/mL is 125 ng/mL or greater.
 3. Themethod of claim 1, wherein the plasma concentration of greater than 100ng/mL is 150 ng/mL or greater.
 4. The method of claim 1, wherein theplasma concentration of greater than 100 ng/mL is 175 ng/mL or greater.5. The method of claim 1, wherein the plasma concentration of greaterthan 100 ng/mL is 200 ng/mL or greater.
 6. The method of claim 1,wherein the plasma concentration of greater than 100 ng/mL is 225 ng/mLor greater.